Prior studies from our lab have identified a role for NUCB2 in regulating the release of the type I, 55-kDa tumor necrosis factor receptor (TNFR1) from cells to the extracellular space, via a mechanism that may involve the regulation of vesicular trafficking. We utilized yeast two-hybrid screens to identify ARTS-1 (aminopeptidase regulator of tumor necrosis factor shedding) as a TNFR1-binding protein and NUCB2 as an ARTS-1-binding protein. NUCB2 (nucleobindin 2) is an EF-hand, helix-loop-helix protein that binds ARTS-1 and thereby participates in the mechanism mediating the release of TNFR1 to the extracellular space (J Biol Chem 2006;281: 6860 6873). NUCB2 and ARTS-1 co-localize with TNFR1 in cytoplasmic vesicles and regulate the release of TNFR1 from cells to the extracellular space by two mechanisms, the proteolytic cleavage of TNFR1 ectodomains and the release of TNFR1 exosome-like vesicles (J Clin Invest 2002;110: 515-526). This project is utilizing NUCB2 knockout mice to investigate the role of this ARTS-1-binding protein in the pathogenesis of experimental murine house dust mite-induced asthma.